Presentation on theme: "Randomized phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas (TRS) Sant P. Chawla,"— Presentation transcript:
1 Randomized phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas (TRS)Sant P. Chawla, Andrew Hendifar, Michael Leahy, Antoine Italiano, Shreyaskumar Patel, Peter Hohenberger, Armando Santoro, Arthur P. Staddon, Nicolas Penel, Sophie Piperno-Neumann, Pilar Lardelli, Antonio Nieto, Carmen Kahatt, Jean-Yves BlayAs the audience knows, trabectedin is a marine derived alkaloid that has demonstrated efficacy in soft tissue sarcoma.This study was conducted to fulfill a specific obligation from the EMA: to identify predictors of response to trabectedin.High response rate of trabectedin in myxoid liposarcomas is well-documented.A trial was performed in order to verify if this higher activity extrapolated to other translocation related sarcomas as compared to doxorubicin containing regimens.
2 Study DesignAn adaptive design in chemonaïve patients with advanced TRS, stratified by performance status and subtype, then randomized to receive:Trabectedin: 1.5 mg/m2 in 24h iv infusion q3wkDoxorubicin based chemotherapy (DXCT): single agent 75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide 6-9 g/m2 q3wkMRCL (n= 40)Other TRS (n= 40)RANDOMIZATION (1:1)Eligible patientsPS= 0PS= 1-2An adaptive design was used as shown80 chemonaïve patients were planned to be enrolled with at least 50% patients with myxoid liposarcoma.Eligible patients were stratified by ECOG performance status and histological subtype (myxoid liposarcoma versus other histologies) and randomized 1:1 to receive trabectedin or doxorubicin based chemotherapy
3 Study ObjectivesPrimary: Progression free survival (PFS) of trabectedin vs DXCTSecondary:PFS at 6 monthsResponse rate (RR)Overall survivalSafetyPFS/RR analyzed by investigator assessment for all randomized patientsPFS/RR analyzed by independent review only for confirmed TRS patientsPrimary efficacy endpoint was progression-free survival.After randomization, translocation was confirmed by FISH.Secondary endpoints included progression-free survival at 6 months, response rates, overall survival and safety.Response rates were analyzed for all randomized patients by investigator assessment and only TRS confirmed patients by independent review
4 Results: Baseline Characteristics Trabectedin (n=61)DXCT (n=60)Age (yr)Median (range)47 (19-78)49 (19-78)SexMale / female36 (59%) / 25 (41%)38 (63%) / 22 (37%)ECOG PS28 (46%)29 (48%)132 (52%)30 (50%)21 (2%)Sarcoma type by InvestigatorMRCL28 (47%)Other33 (54%)32 (53%)Sarcoma type by central pathology23 (38%)17 (28%)20 (33%)Not confirmed*10 (16%)A total of 121 patients were randomized , 61 to trabectedin arm and 60 to doxorubicin-based chemotherapy.Baseline characteristics were well balanced as shownPathological review did not confirm TRS diagnosis and/or translocation in 33 of 121 randomized patients.Therefore, TRS confirmed population consisted of 88 patients: 40 (33%) with MRCL and 48 (40%) with other TRS.* Wrong diagnosis 4 (7%) and 9 (15%) patients of the trabectedin and DXCT arms, no evidence of translocation in 3 (5%) and 2 (3%) patients, and lack of available material for central review in 3 (5%) and 12 (20%) patients
5 Histology According Central Diagnosis (TRS Confirmed Patients N=88) Trabectedin(n=51)DXCT(n=37)N%MYXOID LIPOSARCOMA2345.11745.9SYNOVIAL SARCOMA1529.4924.3ALVEOLAR SOFT PART SARCOMA23.95.4CLEAR CELL SARCOMA35.9410.8DESMOPLASTIC SMALL ROUND CELL12.02.7EXTRASKELETAL MYXOID CHONDROSARCOMA59.8LOW GRADE ENDOMETRIAL STROMAL SARCOMALOW GRADE FIBROMYXOID SARCOMA.As described earlier, almost 50% of patients in either arm had myxoid liposarcomaOther histological sybtypes mainly included synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma and extraskeletal myxoid chondrosarcoma.Ewings and Rhabdomyosarcoma were excluded due to high response rates seen with standard chemotherapy.
6 Results: Baseline Characteristics Trabectedin (n=61)DXCT (n=60)Disease ExtensionLocally advanced18 (30%)13 (22%)Metastatic43 (70%)47 (78%)Prior surgery (radical/palliative)33 (54%)38 (63%)Prior radiotherapy24 (39%)21 (35%)Number of sites involved at baseline, Median (range)2 (1-8)2 (1-5)Months from first diagnosis to randomization, Median (range)10 (1-187)8 (0-310)Patients with advanced or metastatic disease as well as patients receiving prior surgery and radiotherapy were also balanced as shown.
7 Patient ExposureTrabectedin (n=61)DXCT (n=57)Number of cycles441264Number of cycles per patientMedian (range)5 (1-31)6 (1-8)Doxorubicinsingle agent(n=36)plus ifosfamide(n=21)4 (1-8)Time on treatment (weeks)19.3 ( )19.2 ( )14.3 ( )Median number of cycles was similar in both treatment arms but trabectedin could be administered indefinitely due to its lack of cumulative toxicities.
8 Censoring A high percentage of patients were censored in both arms Main reasons for censoring:Surgical removal of lesions24% in trabectedin arm and 16% in the DXCT armAdministration of a new anticancer therapy (chemotherapy or radiotherapy) before progression of the disease18% in trabectedin arm and 24% in DXCT armImportantly, 35-40% patients in either arm ended up receiving the drug in the other armPatients in trabectedin arm also received DXCTPatients in DXCT arm also received trabectedinA high percentage of patients were censored in both treatment arms rendering the analyses underpowered. Censoring rate was balanced between both arms.Main censoring reason was surgical lesion removal before disease progressionOther frequent censoring reason was administration of other anticancer therapy or radiotherapy before disease progressionImportantly, 35-40% patients in either arm received the opposite drug.Patients in the trabectedin arm received doxorubicin based chemotherapy and vice-versa.
9 Results: Response Rate Investigator AssessmentAll randomized patientsTrabectedin (n=61)DXCT (n=60)Best objective response (RECIST)PR5 (8%)15 (25%)0.0150SD40 (66%)33 (55%)DCR45 (74%)48 (80%)PD11 (18%)8 (13%)NE4 (7%)For all randomized patients, partial responses by RECIST were significantly higher in the doxorubicin based chemotherapy arm. But overall disease control rate was similar; 75% in both arms.
10 Results: Response Rate Independent Review TRS confirmed patientsTrabectedin (n=51)DXCT(n=37)p-valueBest objective response (RECIST)PR3 (6%)10 (27%)0.0123SD39 (77%)22 (60%)DCR42 (82%)32 (87%)PD6 (12%)1 (3%)NE4 (11%)Histology of PR patients2 MRCL1 Synovial5 MRCL4 Synovial1 Desmoplastic Round cellFor TRS confirmed patients, partial response rates were significantly higher for the doxorubicin based chemotherapy arm. However, disease control rate was again similar; 85% in both arms.Response rates in the TRS confirmed patients were similar to the rates for all randomized patients.In the Trabectedin arm, out of 3 patients who had partial response, 2 were Myxoid round cell liposarcomas and 1 was synovial sarcomaIn the doxorubicin based chemotherapy arm, out of 10 patients who had PR, 5 were again myxoid round cell LPS, 4 were synovial sarcomas and 1 was a desmoplastic round cell sarcoma
11 Results: PFS by Investigators Median: 16.1 months (95% CI, )Hazard ratio: 0.85, p= Log rank p=0.5533Median: 8.8 months (95% CI, )For all randomized patients, median PFS was 16 months in trabectedin arm versus 9 months in doxorubicin based chemotherapy arm, but given the high rate of censoring, was not statistically significant.
12 Results: PFS by Independent Review Hazard ratio: 0.86; p= Stratified log-rank p=0.9573Median: 18.8 months (95% CI, 5.7-not reached)Median: 8.3 months (95% CI, )For TRS confirmed patients, median PFS was 19 months in trabectedin arm versus 8 months in doxorubicin based chemotherapy arm, but again, given the high censoring, was not statistically significant.
13 Results: Overall Survival Median: 27.3 months (95% CI, )Median: 38.9 months (95% CI, 24.2-nr)Hazard ratio: 0.77, p= Log rank p=0.3659For all randomized patients, median overall survival was 39 months in trabectedin arm vs 27 months in doxorubicin- based chemotherapy arm, but was not statistically significant due to the high rate of censoringSurvival curves separated in favor of trabectedin after 20 months.
14 OS in Myxoid Liposarcoma In subset analysis, which may not be kosher for the statistical aficionados in the audience, overall survival appears longer in patients with myxoid liposarcoma, but may not be valid due to the high censoring.Median: 95% CI (-)Median: % CI ( )Hazard ratio: 0.25, p= Log rank p=0.0314
15 Results: Hematologic and Other Laboratory Toxicity TrabectedinDXCTGrade1-2 (%)Grade 3-4 (%)Laboratory disordersNeutropenia25.0%55.0%10.7%75%Febrile neutropenia-1.6%12.3%Thrombocytopenia26.2%16.4%37.5%14.3%ALT increase40.0%53.3%37.0%1.9%AST increase51.7%33.3%ALKP increase56.7%5.0%38.9%Bilirubin increase20.0%1.7%13.0%CPK increase34.5%8.6%8.2%4.1%Incidence of grade 3/4 neutropenia was higher in doxorubicin armThe most common severe laboratory abnormality associated with trabectedin was transient transaminases elevation
16 Results: Non-Hematologic Toxicity TrabectedinDXCTGrade1-2 (%)Grade 3-4 (%)Treatment related AEsFatigue59.0%6.5%61.4%1.8%Nausea68.9%1.6%64.9%-Vomiting42.6%26.3%Mucositis4.9%8.8%Alopecia43.9%As expected, severe fatigue was seen more frequently in trabectedin arm while febrile neutropenia and mucositis were more commonly observed in doxorubicin-based chemotherapy arm.
17 SummaryThe study was underpowered to detect any statistical significant differences in the two arms due to high rate of censoring in both armsOverall, no statistically significant differences in PFS/OS were observedMedian PFS was 19 mo. in trabectedin arm vs. 8 mo. in DXCT armMedian OS was 39 mo. in trabectedin arm vs. 27 mo. in DXCT armSafety profiles for trabectedin and DXCT were consistent with previous studiesAbility to administer trabectedin over prolonged periods without cumulative toxicity may allow for longer disease controlTrabectedin should be further explored in a definitive randomized study in myxoid liposarcoma patientsHigh rate of censoring in both arms rendered the study underpowered to detect any statistically significant differences.No statistical significant differences were observed in PFS or OS.As expected, safety profiles for both arms was consistent with previous studiesThe ability to administer multiple cycles of trabectedin without significant cumulative toxicity may allow for longer disease controlTrabectedin deserves further exploration in a definitive randomized study in myxoid liposarcoma patients
19 All randomized patients Censoring ReasonsEfficacy populationTrabectedin (n=51)DXCT (n=37)Surgery12 (24%)6 (16%)Chemotherapy6 (12%)7 (19%)Radiotherapy3 (6%)2 (5%)Last tumor assessmenta5 (14%)Otherb2 (4%)4 (11%)Total35 (69%)24 (65%)All randomized patientsTrabectedin (n=61)DXCT(n=60)11 (18%)12 (20%)5 (8%)4 (7%)3 (5%)6 (10%)9 (15%)32 (52%)34 (57%)a Patients on follow-up for disease assessment or with event/subsequent therapy out of study window or without PD at last tumor assessment available in database at cut-off date.b Censored at randomization (e.g.: untreated) or withdrawn due to related/unrelated adverse event or refusal before treatment onset/disease progression or new treatment out of study window.Censoring rates were similar in both arms for both the primary efficacy population and the all randomized population. Surgical removal of the lesions was the most common reason for censure, and was similar in trabectedin and in Doxo-based chemotherapy arms.
20 Subsequent Chemotherapy Agents in Censored Patients Trabectedin(n=35)DXCT(n=24)N%CEDIRANIB.14.2CYCLOPHOSPHAMIDE25.78.3DACARBAZINEDOCETAXEL38.6DOXORUBICIN1028.612.5DOXORUBICIN HYDROCHLORIDEEPIRUBICIN2.9ETOPOSIDEGEMCITABINE514.3IFOSFAMIDE617.1833.3PAZOPANIBSORAFENIBSORAFENIB TOSILATESUNITINIBTRABECTEDIN411.4937.5VINORELBINEVORINOSTATChemotherapy agents given to patients with no disease progression, in both treatment arms. Patients were therefore censored for PFS.
21 Responders’ Histology PatientTreatment armCentral Diagnosis103013TrabectedinSynovial sarcoma182003Myxoid liposarcoma21021103008DXCT14034Desmoplastic small round cell sarcoma1840251910062210113301444016710207102672011Histological subtype of sarcoma in patients who responded by RECIST (Independent Review).
22 Discontinuations and Dose Reductions Trabectedin (n=61)DXCT (n=57)n%NDeaths associated with treatment- related AEs11.61.8Discontinuations associated with treatment-related AEs1016.4610.5Delays associated with treatment- related AEs3252.5814.0Dose reductions associated with treatment-related AEs2439.4Administration delays and dose reductions occurred more frequently in the trabectedin arm, partially due to the prolonged treatment duration.Transaminase increase was the main reason for dose reduction.Neutropenia was the most common cause of administration delay. Neutropenia was controlled in trabectedin arm mainly with dose delay, while G-CSF was more frequently administered in Doxo arm (61.4% of patients) than in trabectedin arm (49.2%).Administration delays and dose reductions occurred more frequently in the trabectedin arm, partially due to the prolonged treatment duration.Transaminase increase was the main reason for dose reductionNeutropenia was the most common cause of administration delay.
23 Results: Safety in DXCT DXCT+Ifosfamide (n=21)DXCT (n=36)Grade1-2 (%)Grade 3 (%)Grade 4 (%)Grade 4(%)Treatment related AEsFatigue57.1%-63.9%2.8%Nausea52.4%72.2%Vomiting19.0%30.6%Mucositis9.5%4.8%36.1%11.1%Alopecia38.1%47.2%Febrile neutropenia14.3%5.6%Laboratory disordersNeutropenia23.8%42.9%2.9%34.3%Thrombocytopenia45.7%5.7%ALT increase31.6%5.3%40.0%AST increase26.3%Alkaline phosphatase increase52.6%31.4%Bilirubin increase10.5%CPK increase5.9%12.5%3.1%Most frequent adverse events and laboratory abnormalities in patients from arm B (doxo-based chemotherapy), split by treatment type: doxorubicin alone or in combination with ifosfamide.